K-ras is a GTPase protein encoded by the Kirsten rat sarcoma 2 viral oncogene homolog (K-ras) oncogene (also known as K-ras2 or RASK2; PubMed Gene ID # 3845), which belongs to the family of RAS proteins.
The human RAS family consists of three closely related proto-oncogenes: c-Harvey (H)-RAS, c-Kirsten (K)-RAS, and N-RAS, which share 90% of their peptide sequence. RAS proteins are localized in the inner cell membrane, bind GDP and GTP, and possess an intrinsic GTPase activity, implicated in the regulation of their activity. RAS proteins influence proliferation, differentiation, transformation, and apoptosis by relaying mitogenic and growth signals into the cytoplasm and the nucleolus. In a normal cell, most of the RAS molecules are present in an inactive GDP-bound conformation.
K-ras Mutations
Genetic alterations in the K-ras signaling pathway are involved in more than 90% of cases of Pancreatic Cancer (PC) (Réjiba et al, and references cited therein); the majority of such mutations are gain-of-function mutations at codon 12 (K-rasG12D). PC is an aggressive disease, being one of the leading causes of cancer-related death in the western world. Mutations in K-ras are also well known in other cancers. For example, K-ras is involved in the development and progression of colorectal cancer (CRC). Mutations are present in about 40% of CRC cases, most commonly at codons 12 and 13. These mutations prevent dephosphorylation and inactivation of the protein, causing it to be permanently switched on, independently of EGFR-mediated signaling. These mutated K-ras proteins are unlikely be affected by inhibition of EGFR, since the mutation causes the encoded K-ras protein to “freeze” in its active state for a much longer duration than its non-mutated counterpart. Hence, the response to anti-EGFR mABs is strongly reduced in tumors with mutated K-ras (Normanno et al). K-ras mutations also occur in 20-30% of lung cancer patients.
Anti-K-ras Mutations RNAi-based Treatment:
RNAi vectors (Brummelkamp et al) and siRNA against mutated K-ras can lead to apoptosis of cancer cells in vitro and in vivo in mice and reduce tumor growth (Wang et al, Morioka et al, Fleming et al, Réjiba et al, WO2010/001325). Moreover, anti mutated K-ras treatment potentially can slow the epithelial-to-mesenchymal transition (EMT) and thereby slow metastasis of PC disease. For example Singh et al observed an association between epithelial differentiation and tumor cell viability, and that EMT regulators in “K-Ras-addicted” cancers represent candidate therapeutic targets. siRNA (short interfering RNA) have been delivered by millimeter-scale depot technology against mutated K-ras (WO2010/001325 to Shemi) and other non-oncology targets (US2008/0124370 to Marx).